Optimal control in nonequilibrium systems: Dynamic Riemannian geometry of the Ising model.
A general understanding of optimal control in nonequilibrium systems would illuminate the operational principles of biological and artificial nanoscale machines. Recent work has shown that a system driven out of equilibrium by a linear response protocol is endowed with a Riemannian metric related to generalized susceptibilities, and that geodesics on this manifold are the nonequilibrium control protocols with the lowest achievable dissipation. While this elegant mathematical framework has inspired numerous studies of exactly solvable systems, no description of the thermodynamic geometry yet exists when the metric cannot be derived analytically. Herein, we numerically construct the dynamic metric of the two-dimensional Ising model in order to study optimal protocols for reversing the net magnetization.


Determinants of affinity and proteolytic stability in interactions of Kunitz family protease inhibitors with mesotrypsin.
An important functional property of protein protease inhibitors is their stability to proteolysis. Mesotrypsin is a human trypsin that has been implicated in the proteolytic inactivation of several protein protease inhibitors. We have found that bovine pancreatic trypsin inhibitor (BPTI), a Kunitz protease inhibitor, inhibits mesotrypsin very weakly and is slowly proteolyzed, whereas, despite close sequence and structural homology, the Kunitz protease inhibitor domain of the amyloid precursor protein (APPI) binds to mesotrypsin 100 times more tightly and is cleaved 300 times more rapidly. To define features responsible for these differences, we have assessed the binding and cleavage by mesotrypsin of APPI and BPTI reciprocally mutated at two nonidentical residues that make direct contact with the enzyme. We find that Arg at P(1) (versus Lys) favors both tighter binding and more rapid cleavage, whereas Met (versus Arg) at P'(2) favors tighter binding but has minimal effect on cleavage. Surprisingly, we find that the APPI scaffold greatly enhances proteolytic cleavage rates, independently of the binding loop. We draw thermodynamic additivity cycles analyzing the interdependence of P(1) and P'(2) substitutions and scaffold differences, finding multiple instances in which the contributions of these features are nonadditive. We also report the crystal structure of the mesotrypsin·APPI complex, in which we find that the binding loop of APPI displays evidence of increased mobility compared with BPTI. Our data suggest that the enhanced vulnerability of APPI to mesotrypsin cleavage may derive from sequence differences in the scaffold that propagate increased flexibility and mobility to the binding loop.


Comparison of six different sewage treatment processes--reduction of estrogenic substances and effects on gene expression in exposed male fish.
Treated sewage effluents often contain a mixture of estrogenic compounds in low concentrations. The total combined activity of these, however, may be sufficiently high to affect the reproduction of aquatic vertebrates. The introduction of advanced treatment technologies has been suggested as a way to remove micro-contaminants, including estrogenic substances. In this study, one municipal influent was treated with six different processes in parallel on a semi-large scale in order to assess their potential to reduce substances that could contribute to estrogenic effects in male fish. The effluent from a conventional, activated sludge treatment line was compared to a similarly treated effluent with a final sand-filtering step. The addition of ozonation (15 g O(3)/m(3)), a moving bed biofilm reactor (MBBR) or both in combination was also evaluated. There was also a separate treatment line that was based on a membrane bioreactor. A small battery of hepatic estrogen-responsive genes was measured in the exposed fish using quantitative PCR. Concentrations of steroid estrogens and estrogenic phenols in the effluents were measured by GC-ECNI-MS. The ozonated effluents were the only tested effluents for which all measured biological effects in exposed fish were removed. Chemical data suggested that the MBBR technology was equally effective in removing the analyzed estrogens; however, elevated expression of estrogen-responsive genes suggested that some estrogenic substances were still present in the effluent. The membrane bioreactor removed most of the measured estrogens and it reduced the induction of the estrogen-responsive genes. However, fish exposed to this effluent had significantly enlarged livers. Given that the same influent was treated in parallel with a broad set of technologies and that the chemical analyses were combined with an in vivo assessment of estrogenic responses, this study provides valuable input into the assessment of advanced treatment processes for removing estrogenic substances.


Persistence of pregabalin treatment in Taiwan: a nation-wide population-based study.
Pregabalin is approved for the treatment of neuropathic pain, fibromyalgia, and seizure disorders, although the pivotal trials were mostly carried out in Europe or North America. The prescribing patterns among different indications in Asia have rarely been explored. This was a population-based retrospective cohort study based on the National Health Insurance Research Database in Taiwan. Prescriptions of pregabalin were identified, and data regarding demographics, indications, co-existing diagnoses, and concomitant medications were extracted. Pregabalin users were followed for at least one year, and factors associated with persistence at one year were determined by using multivariate logistic regression analysis. Between June 2012 and December 2016, 114,437 pregabalin users (mean age 60.7 ± 15.4 years, 57.8% female) were identified. The indications included post-herpetic neuralgia (PHN) (30.5%), musculoskeletal diseases other than fibromyalgia (21.2%), fibromyalgia (18.4%), diabetic peripheral neuropathic pain (DPNP) (11.7%) and epilepsy (2.9%). Overall, 62.5% and 6.4% of patients achieved a maximum dose of ≥150 and ≥ 300 mg/day, respectively. The median duration of persistent pregabalin use was 28 days (interquartile range 14-118 days). The one-year persistence rate was 12.1%, and the indications associated with the highest and lowest persistence rates were epilepsy (42.4%) and PHN (6.1%), respectively. Male gender (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.09-1.18), older age (OR 1.01 per year, 95% CI 1.01-1.01), indications other than PHN, especially epilepsy (OR 8.04, 95% CI 7.33-8.81, PHN as reference), and a higher initial dose (OR 1.12 per 75 mg, 95% CI = 1.10-1.15) were associated with persistence at one year, whereas the initial concomitant use of antiviral agents decreased the likelihood (OR 0.41, 95% CI 0.35-0.47). Pregabalin prescriptions for pain disorders were limited to short-term use, which is consistent around the world. However, the average prescribed dose in Taiwan was lower than those in Western countries, and was frequently below the recommended ranges. Potential causes included the duration of natural history of PHN, and off-label prescriptions for pain in acute herpes zoster, rather than PHN, as well as intolerance to the side effects.


3d-4f {Co(II)3Ln(OR)4} Cubanes as Bio-Inspired Water Oxidation Catalysts.
Although the {CaMn4O5} oxygen evolving complex (OEC) of photosystem II is a major paradigm for water oxidation catalyst (WOC) development, the comprehensive translation of its key features into active molecular WOCs remains challenging. The [Co(II)3Ln(hmp)4(OAc)5H2O] ({Co(II)3Ln(OR)4}; Ln = Ho-Yb, hmp = 2-(hydroxymethyl)pyridine) cubane WOC series is introduced as a new springboard to address crucial design parameters, ranging from nuclearity and redox-inactive promoters to operational stability and ligand exchange properties. The {Co(II)3Ln(OR)4} cubanes promote bioinspired WOC design by newly combining Ln(3+) centers as redox-inactive Ca(2+) analogues with flexible aqua-/acetate ligands into active and stable WOCs (max. TON/TOF values of 211/9 s(-1)). Furthermore, they open up the important family of 3d-4f complexes for photocatalytic applications. The stability of the {Co(II)3Ln(OR)4} WOCs under photocatalytic conditions is demonstrated with a comprehensive analytical strategy including trace metal analyses and solution-based X-ray absorption spectroscopy (XAS) investigations. The productive influence of the Ln(3+) centers is linked to favorable ligand mobility, and the experimental trends are substantiated with Born-Oppenheimer molecular dynamics studies.


The mouse Gene Expression Database (GXD): 2011 update.
The Gene Expression Database (GXD) is a community resource of mouse developmental expression information. GXD integrates different types of expression data at the transcript and protein level and captures expression information from many different mouse strains and mutants. GXD places these data in the larger biological context through integration with other Mouse Genome Informatics (MGI) resources and interconnections with many other databases. Web-based query forms support simple or complex searches that take advantage of all these integrated data. The data in GXD are obtained from the literature, from individual laboratories, and from large-scale data providers. All data are annotated and reviewed by GXD curators. Since the last report, the GXD data content has increased significantly, the interface and data displays have been improved, new querying capabilities were implemented, and links to other expression resources were added. GXD is available through the MGI web site (www.informatics.jax.org), or directly at www.informatics.jax.org/expression.shtml.


A scale of risk.
This article proposes a conceptual framework for ranking the relative gravity of diverse risks. This framework identifies the moral considerations that should inform the evaluation and comparison of diverse risks. A common definition of risk includes two dimensions: the probability of occurrence and the associated consequences of a set of hazardous scenarios. This article first expands this definition to include a third dimension: the source of a risk. The source of a risk refers to the agents involved in the creation or maintenance of a risk and captures a central moral concern about risks. Then, a scale of risk is proposed to categorize risks along a multidimensional ranking, based on a comparative evaluation of the consequences, probability, and source of a given risk. A risk is ranked higher on the scale the larger the consequences, the greater the probability, and the more morally culpable the source. The information from the proposed comparative evaluation of risks can inform the selection of priorities for risk mitigation.


The coevolution of the firm and the product attribute space.
Traditionally, firm competition has been studied in contexts where the dimensionality of the product attribute space is given, and firms deploy their strategies constrained by this space. However, firms may exert influence on the local structure of the product attribute space by offering product variants with new attributes. As a result, the geometry of the product attribute space would change endogenously through firms' actions, and this emergent new geometry modifies the conditions for subsequent firm behavior. By focusing on this interplay between actors and conditions, we explore the co-evolution of the firm and the product attribute space. Through a multi-variant Cournot competition framework, we develop a computational model in which firms invest to differentiate their products from other variants, but as minimally as possible so that demand from closely similar existing variants can be stolen. We introduce the fraction dimensionality of the attribute space as our critical independent variable, to reflect saturation of the space with product varieties. The simulation reveals that while new product variants are typically introduced by firms with scale economies, their performance gap with firms without scale economies reduces as fraction dimensionality increases. This indicates that space geometry evolution may favor small-scale players, even when their large-scale competitors are the driving force behind attribute space changes.


Highly respirable dry powder inhalable formulation of voriconazole with enhanced pulmonary bioavailability.
To develop and characterize a highly respirable dry powder inhalable formulation of voriconazole (VRZ). Powders were prepared by spray drying aqueous/alcohol solutions. Formulations were characterized in terms of particle size, morphology, thermal, moisture responses and aerosolization performance. Optimized powder was deposited onto an air-interface Calu-3 model to assess their uptake across Calu-3 lung epithelia. Optimized formulation was evaluated for stability (drug content and aerosol performance) for 3 months. Additionally, Calu-3 cell viability, lung bioavailability and tissue distribution of optimized formulation were evaluated. Particle size and aerosol performance of dry powder containing 80% w/w VRZ and 20% w/w leucine was appropriate for inhalation therapy. Optimized formulation showed irregular morphology, crystalline nature, low moisture sensitivity and was stable for 3 months at room temperature. Leucine did not alter the transport kinetics of VRZ, as evaluated by air-interface Calu-3 model. Formulation was non-cytotoxic to pulmonary epithelial cells. Moreover, lung bioavailability and tissue distribution studies in murine model clearly showed that VRZ dry powder inhalable formulation has potential to enhance therapeutic efficacy at the pulmonary infection site whilst minimizing systemic exposure and related toxicity. This study supports the potential of inhaled dry powder VRZ for the treatment of fungal infections.


Multidrug resistance in Klebsiella pneumoniae: a novel gene, ramA, confers a multidrug resistance phenotype in Escherichia coli.
Spontaneous multidrug-resistant (Mdr) mutants of Klebsiella pneumoniae strain ECL8 arose at a frequency of 2.2 x 10(-8) and showed increased resistance to a range of unrelated antibiotics, including chloramphenicol, tetracycline, nalidixic acid, ampicillin, norfloxacin, trimethoprim and puromycin. A chromosomal fragment from one such mutant was cloned, and found to confer an Mdr phenotype on Escherichia coli K12 cells that was essentially identical to that of the K. pneumoniae mutant. Almost complete loss of the OmpF porin in the E. coli transformant, and of the corresponding porin in the K. pneumoniae mutant, was observed. The presence of the Mdr mutation in K. pneumoniae or the cloned K. pneumoniae ramA (resistance antibiotic multiple) locus in E. coli also resulted in active efflux of tetracycline, and increased active efflux of chloramphenicol. After transformation of a ramA plasmid into E. coli, expression of chloramphenicol resistance occurred later than expression of resistance to tetracycline, puromycin, trimethoprim and nalidixic acid. The ramA gene was localized and sequenced. It encodes a putative positive transcriptional activator that is weakly related to the E. coli MarA and SoxS proteins. A ramA gene was also found to be present in an Enterobacter cloacae fragment that has previously been shown to confer an Mdr phenotype, and it appears that ramA, rather than the romA gene identified in that study, is responsible for multidrug resistance. The ramA gene from the wild-type K. pneumoniae was identical to that of the mutant strain and also conferred an Mdr phenotype on E. coli, indicating that the mutation responsible for Mdr in K. pneumoniae had not been cloned.


Protective effect of ferulic acid on cisplatin induced nephrotoxicity in rats.
This study aims to determine the potential protective effects of ferulic acid against cisplatin-induced nephrotoxicity and to compare its effect with curcumin, a well-known protective agent against cisplatin- induced toxicity in rats. Administration of cisplatin resulted in high BUN (Blood Urea Nitrogen), creatinine, MDA (Malondialdehyde), MPO (Myeloperoxidase), TOS (Total Oxidative Status), PtNT (Protein Nitrotyrosine) levels (p<0.05). Histological observations showed abnormal morphology of kidney; in addition with appearance of TUNEL positive cells indicating apoptosis in cisplatin administered group. HO-1 (Heme Oxygenase-1) levels measured by RT-PCR (Real Time Polymerase Chain Reaction), and TAS (Total Antioxidative Status) revealed antioxidant depletion due to cisplatin toxicity in animals (p<0.05). All parameters showed improvement in groups treated with ferulic acid (p<0.05). Ferulic acid treatment was found significant in preventing oxidative stress, increasing antioxidative status and regaining histological parameters to normal, indicating nephroprotective and antioxidant effects of this phenolic compound.


Analysis of Knee Joint Line Obliquity after High Tibial Osteotomy.
The aim of this study was to evaluate which lower extremity alignment (knee and ankle joint) parameters affect knee joint line obliquity (KJLO) in the coronal plane after open wedge high tibial osteotomy (OWHTO). Overall, 69 knees of patients that underwent OWHTO were evaluated using radiographs obtained preoperatively and from 6 weeks to 3 months postoperatively. We measured multiple parameters of knee and ankle joint alignment (hip-knee-ankle angle [HKA], joint line height [JLH], posterior tibial slope [PS], femoral condyle-tibial plateau angle [FCTP], medial proximal tibial angle [MPTA], mechanical lateral distal femoral angle [mLDFA], KJLO, talar tilt angle [TTA], ankle joint obliquity [AJO], and the lateral distal tibial ground surface angle [LDTGA]; preoperative [-pre], postoperative [-post], and the difference between -pre and -post values [-Δ]). We categorized patients into two groups according to the KJLO-post value (the normal group [within ± 4 degrees, 56 knees] and the abnormal group [greater than ± 4 degrees, 13 knees]), and compared their -pre parameters. Multiple logistic regression analysis was used to examine the contribution of the -pre parameters to abnormal KJLO-post. The mean HKA-Δ (-9.4 ± 4.7 degrees) was larger than the mean KJLO-Δ (-2.1 ± 3.2 degrees). The knee joint alignment parameters (the HKA-pre, FCTP-pre) differed significantly between the two groups (p < 0.05). In addition, the HKA-pre (odds ratio [OR] = 1.27, p = 0.006) and FCTP-pre (OR = 2.13, p = 0.006) were significant predictors of abnormal KJLO-post. However, -pre ankle joint parameters (TTA, AJO, and LDTGA) did not differ significantly between the two groups and were not significantly associated with the abnormal KJLO-post. The -pre knee joint alignment and knee joint convergence angle evaluated by HKA-pre and FCTP-pre angle, respectively, were significant predictors of abnormal KJLO after OWHTO. However, -pre ankle joint parameters were not significantly associated with abnormal KJLO after OWHTO.


Anti-inflammatory potential of allyl-isothiocyanate--role of Nrf2, NF-(κ) B and microRNA-155.
In this study, the underlying mechanisms of the potential anti-inflammatory properties of allyl-isothiocyanate (AITC) were analysed in vitro and in vivo. Murine RAW264.7 macrophages stimulated with lipopolysaccharide (LPS) were supplemented with increasing concentrations of AITC. In addition, C57BL/6 mice (n= 10 per group) were fed a pro-inflammatory high-fat diet and AITC was administered orally via gavage for 7 days. Biomarkers of inflammation were determined both in cultured cells and in mice. AITC significantly decreased tumour necrosis factor α mRNA levels and its secretion in LPS stimulated RAW264.7 macrophages. Furthermore, gene expression of other pro-inflammatory markers including interleukin-1β and inducible nitric oxide synthase were down-regulated following AITC treatment. AITC decreased nuclear p65 protein levels, a subunit of the transcription factor NF-κB. Importantly, our data indicate that AITC significantly attenuated microRNA-155 levels in LPS-stimulated RAW264.7 macrophages in a dose-dependent manner. The anti-inflammatory effects of AITC were accompanied by an increase in Nrf2 nuclear translocation and consequently by an increase of mRNA and protein levels of the Nrf2 target gene heme-oxygenase 1. AITC was slightly less potent than sulforaphane (used as a positive control) in down-regulating inflammation in LPS-stimulated macrophages. A significant increase in nuclear Nrf2 and heme-oxygenase 1 gene expression and only a moderate down-regulation of interleukin-1β and microRNA-155 levels due to AITC was found in mouse liver. Present data suggest that AITC exhibits potent anti-inflammatory activity in cultured macrophages in vitro but has only little anti-inflammatory activity in mice in vivo.


The effects of a high protein diet on indices of health and body composition--a crossover trial in resistance-trained men.
Eight weeks of a high protein diet (>3 g/kg/day) coupled with a periodized heavy resistance training program has been shown to positively affect body composition with no deleterious effects on health. Using a randomized, crossover design, resistance-trained male subjects underwent a 16-week intervention (i.e., two 8-week periods) in which they consumed either their normal (i.e., habitual) or a higher protein diet (>3 g/kg/day). Thus, the purpose of this study was to ascertain if significantly increasing protein intake would affect clinical markers of health (i.e., lipids, kidney function, etc.) as well as performance and body composition in young males with extensive resistance training experience. Twelve healthy resistance-trained men volunteered for this study (mean ± SD: age 25.9 ± 3.7 years; height 178.0 ± 8.5 cm; years of resistance training experience 7.6 ± 3.6) with 11 subjects completing most of the assessments. In a randomized crossover trial, subjects were tested at baseline and after two 8-week treatment periods (i.e., habitual [normal] diet and high protein diet) for body composition, measures of health (i.e., blood lipids, comprehensive metabolic panel) and performance. Each subject maintained a food diary for the 16-week treatment period (i.e., 8 weeks on their normal or habitual diet and 8 weeks on a high protein diet). Each subject provided a food diary of two weekdays and one weekend day per week. In addition, subjects kept a diary of their training regimen that was used to calculate total work performed. During the normal and high protein phase of the treatment period, subjects consumed 2.6 ± 0.8 and 3.3 ± 0.8 g/kg/day of dietary protein, respectively. The mean protein intake over the 4-month period was 2.9 ± 0.9 g/kg/day. The high protein group consumed significantly more calories and protein (p < 0.05) than the normal protein group. There were no differences in dietary intake between the groups for any other measure. Moreover, there were no significant changes in body composition or markers of health in either group. There were no side effects (i.e., blood lipids, glucose, renal, kidney function etc.) regarding high protein consumption. In resistance-trained young men who do not significantly alter their training regimen, consuming a high protein diet (2.6 to 3.3 g/kg/day) over a 4-month period has no effect on blood lipids or markers of renal and hepatic function. Nor were there any changes in performance or body composition. This is the first crossover trial using resistance-trained subjects in which the elevation of protein intake to over four times the recommended dietary allowance has shown no harmful effects.


MOXI Is a Mitochondrial Micropeptide That Enhances Fatty Acid β-Oxidation.
Micropeptide regulator of β-oxidation (MOXI) is a conserved muscle-enriched protein encoded by an RNA transcript misannotated as non-coding. MOXI localizes to the inner mitochondrial membrane where it associates with the mitochondrial trifunctional protein, an enzyme complex that plays a critical role in fatty acid β-oxidation. Isolated heart and skeletal muscle mitochondria from MOXI knockout mice exhibit a diminished ability to metabolize fatty acids, while transgenic MOXI overexpression leads to enhanced β-oxidation. Additionally, hearts from MOXI knockout mice preferentially oxidize carbohydrates over fatty acids in an isolated perfused heart system compared to wild-type (WT) animals. MOXI knockout mice also exhibit a profound reduction in exercise capacity, highlighting the role of MOXI in metabolic control. The functional characterization of MOXI provides insight into the regulation of mitochondrial metabolism and energy homeostasis and underscores the regulatory potential of additional micropeptides that have yet to be identified.


Mindfulness training promotes upward spirals of positive affect and cognition: multilevel and autoregressive latent trajectory modeling analyses.
Recent theory suggests that positive psychological processes integral to health may be energized through the self-reinforcing dynamics of an upward spiral to counter emotion dysregulation. The present study examined positive emotion-cognition interactions among individuals in partial remission from depression who had been randomly assigned to treatment with mindfulness-based cognitive therapy (MBCT; n = 64) or a waitlist control condition (n = 66). We hypothesized that MBCT stimulates upward spirals by increasing positive affect and positive cognition. Experience sampling assessed changes in affect and cognition during 6 days before and after treatment, which were analyzed with a series of multilevel and autoregressive latent trajectory models. Findings suggest that MBCT was associated with significant increases in trait positive affect and momentary positive cognition, which were preserved through autoregressive and cross-lagged effects driven by global emotional tone. Findings suggest that daily positive affect and cognition are maintained by an upward spiral that might be promoted by mindfulness training.


Status does not predict stress among Hadza hunter-gatherer men.
In recent years there has been much research regarding the extent to which social status is related to long-term indices of health. The majority of studies looking at the interplay between social status and health have been conducted in industrialized societies. However, it has been argued that most of human evolution took place in small, mobile and egalitarian hunter-gatherer groups where individuals exhibited very little variation in terms of material wealth or possessions. In this study, we looked at the extent to which two domains of social status, hunting reputation (being perceived as a good hunter) and popularity (being perceived as a friend), are related to physiological stress levels among Hadza men, hunter-gatherers living in Northern Tanzania. The results of our study show that neither hunting reputation nor popularity is associated with stress levels. Overall, our data suggest that, in at least some traditional small-scale societies exhibiting an egalitarian social model, such as the Hadza, the variation in social status measures based on both popularity and hunting reputation does not translate into one of the commonly used indices of wellbeing.


The problem of animal consciousness in relation to neuropsychology.
It is argued that experimental analyses of changes in sensory awareness require not only a measure of discrimination, but a separate commentary or classificatory judgment by subject. In human blindsight there is a dissociation between successful discrimination, on the one hand, and a commentary which acknowledges no awareness of the discriminanda, on the other. Comparable judgments should be possible, in principle, in animal studies of blindsight and other neurological dissociations in which there is retention of function in the absence of awareness. Important animal studies are beginning to appear along these lines. Such a procedure also always entails an assumption of normal "awareness". A complementary approach for some situations is the study of intentionality in the context of altered goals.


The anterobithorax and bithorax mutations of the bithorax complex.
The anterobithorax (abx) and bithorax (bx) genes together direct the development of the posterior second and anterior third thoracic segments of the fruit fly. We have characterized the phenotypes and DNA lesions of 19 abx and bx alleles. abx and bx mutations differ both in the nature and location of their DNA lesions, forming two clusters within a relatively small region of the Ultrabithorax transcription unit. Correlation between phenotype and DNA lesion suggests the presence of two or more genetic elements in this region distinct from the Ultrabithorax transcript. Mutant transformations do not strictly obey segmental or parasegmental boundaries. Most of the bx mutations result from insertions of the mobile element gypsy. The strength of these alleles varies in a regular way dependent on the position and orientation of the gypsy element. We propose models for gypsy element action and bithorax complex expression in the light of these results.


Evaluation of climate change adaptation in the energy generation sector in Colombia via a composite index - A monitoring tool for government policies and actions.
The aim of the article is to evaluate the national adaptation to climate change in the energy generation sector in Colombia via a composite index. To build an index, a framework by stages is used, which includes the definition of the main concepts that supports the measurements; the selection of the relevant indicators using a subject matter experts; standardization of the indicators using a mathematic formula regarding the relationship between the variables that represent the adaptation to climate change; and establishment of the weights using an analytic hierarchical process of paired comparisons and the aggregation of indicators to obtain the following three sub-indexes: reactive adaptation, wherein the replacement of hydraulic energy by thermal energy is evaluated; anticipatory adaptation, which measures the gap between the generation of total energy and the demand of the national energy system; and planned adaptation, which considers indicators such as the sectoral plan for adapting to climate change, the law of alternative energies, and the generation of alternative energies as a percentage of generation capacity. By adding these sub-indices, the climate change adaptation index (CCAI) is obtained. The results of CCAI show that progress was made from a reactive adaptation scenario in which the system vulnerability was high to an anticipatory adaptation scenario wherein the vulnerability was average, indicating that the foundations for this sector to build a planned adaptation are currently being laid.


Vaccines for preventing HPV-related anogenital infection and neoplasia.
Human papillomavirus (HPV) is a common sexually transmitted pathogen. Although most anogenital HPV infections resolve within several years, persistent infection may lead to neoplasia of the cervix, vagina, vulva, anus, and penis, and also genital warts. High-risk HPV types 16 and 18 are known to cause approximately 70% of all cervical cancers, and low-risk HPV types 6 and 11 are the main causes of genital warts. Prophylactic HPV vaccines have the potential to block the acquisition of HPV and hence subsequent development of anogenital neoplasia. Results from several clinical trials have demonstrated that the HPV L1 virus-like-particle vaccines are safe and highly immunogenic. These trials have documented a 100% vaccine efficacy in prevention of persistent HPV infection and, more important, of HPV-associated anogenital neoplasia in per-protocol analyses. Widespread vaccination of sexually naïve preadolescent children could substantially reduce the morbidity and mortality associated with anogenital malignancies. Furthermore, such a primary prevention program would also reduce healthcare costs.


Strategies for enhancement of transcranial magnetic stimulation effects in tinnitus patients.
Tinnitus is an auditory phantom sensation characterized by the perception of elementary sound or noise in the absence of any acoustical sound source. Tinnitus is a frequent disorder and is difficult to treat. Compelling evidence corroborates the perception of chronic tinnitus as associated with regional changes in cortical excitability. Repetitive transcranial magnetic stimulation (rTMS) over the temporal or the temporoparietal cortex has recently been introduced as a new treatment strategy for tinnitus. The technique has been applied in two different ways in tinnitus patients. Single sessions of high-frequency rTMS have been successful in transient reduction of tinnitus perception, whereas repeated sessions of low-frequency rTMS have resulted in longer-lasting tinnitus reduction, indicating therapeutic potential. However, treatment outcome so far is characterized by high interindividual variability and only moderate effect size. This study reviews different approaches for enhancement of rTMS effects in tinnitus patients. The different strategies include the combined stimulation of nonauditory and auditory brain areas, the variation of stimulation frequencies and intensities, and the comparison of different firing modes (burst vs. tonic stimulation). Furthermore, the value of optimum patient selection is discussed. Another approach consists of a combination of rTMS administration with pharmacological intervention. Repetition of rTMS treatment in treatment responders seems to be a promising approach for the prolongation of treatment effects. A pilot study suggests further that treatment effects can be enhanced by combined stimulation of auditory and nonauditory brain areas. Moreover, clinical data such as tinnitus duration and the dimension of hearing loss seem to have an important impact on treatment effects. Successful enhancement of treatment effects will depend on a more detailed understanding of the neuronal correlates of the different forms of tinnitus and the mechanisms by which rTMS exerts its effects.


Translational molecular imaging for cancer.
Although most clinical diagnostic imaging studies employ anatomic techniques such as computed tomography (CT) and magnetic resonance (MR) imaging, much of radiology research currently focuses on adapting these conventional methods to physiologic imaging as well as on introducing new techniques and probes for studying processes at the cellular and molecular levels in vivo, i.e. molecular imaging. Molecular imaging promises to provide new methods for the early detection of cancer and support for personalized cancer therapy. Although molecular imaging has been practiced in various incarnations for over 20 years in the context of nuclear medicine, other imaging modalities have only recently been applied to the noninvasive assessment of physiology and molecular events. Nevertheless, there has been sufficient experience with specifically targeted contrast agents and high-resolution techniques for MR imaging and other modalities that we must begin moving these new technologies from the laboratory to the clinic. This brief review outlines several of the more promising areas of pursuit in molecular imaging for oncology with an emphasis on those that show the most immediate likelihood for clinical translation.


Nurse-Enhanced Memory Intervention in Heart Failure: the MEMOIR study.
Many patients with heart failure (HF) have cognitive deficits, including memory loss. The aim of this study was to evaluate the efficacy of a cognitive training intervention on memory (primary outcome), working memory, psychomotor speed, executive function, and performance of cognitive activities and instrumental activities of daily living (IADLs). Forty patients with HF were randomly assigned to the computerized plasticity-based cognitive training intervention called Brain Fitness or to the health education active control intervention. Advanced practice nurses made weekly home visits to assess symptoms and monitor intervention adherence. Patients completed demographic and clinical data (baseline), neuropsychologic tests (baseline and 8 and 12 weeks), and measures of cognitive and IADLs performance (baseline and 12 weeks) and satisfaction (12 weeks). Linear mixed models analyses indicated a significant group by time interaction for delayed recall memory (P = .032) and a significant time effect for total (list learning) (P < .001) and delayed (P = .015) recall memory, psychomotor speed (P = .029), and performance of IADLs (P = .006). Intervention adherence and patient satisfaction were high. To our knowledge, this was the first test of Brain Fitness in HF. Although it was a preliminary study with limitations, results support the need for a larger randomized controlled trial to determine whether the memory loss of HF is amenable to plasticity-based interventions.


An extracellular Staphylococcus epidermidis polysaccharide: relation to Polysaccharide Intercellular Adhesin and its implication in phagocytosis.
The skin commensal and opportunistic pathogen Staphylococcus epidermidis is a leading cause of hospital-acquired and biomaterial-associated infections. The polysaccharide intercellular adhesin (PIA), a homoglycan composed of β-1,6-linked N-acetylglucosamine residues, synthesized by enzymes encoded in icaADBC is a major functional factor in biofilm accumulation, promoting virulence in experimental biomaterial-associated S. epidermidis infection. Extracellular mucous layer extracts of S. epidermidis contain another major polysaccharide, referred to as 20-kDa polysaccharide (20-kDaPS), composed mainly out of glucose, N-acetylglucosamine, and being partially sulfated. 20-kDaPS antiserum prevents adhesion of S. epidermidis on endothelial cells and development of experimental keratitis in rabbits. Here we provide experimental evidence that 20-kDaPS and PIA represent distinct molecules and that 20-kDaPS is implicated in endocytosis of S. epidermidis bacterial cells by human monocyte-derived macrophages. Analysis of 75 clinical coagulase-negative staphylococci from blood-cultures and central venous catheter tips indicated that 20-kDaPS is expressed exclusively in S. epidermidis but not in other coagulase-negative staphylococcal species. Tn917-insertion in various locations in icaADBC in mutants M10, M22, M23, and M24 of S. epidermidis 1457 are abolished for PIA synthesis, while 20-kDaPS expression appears unaltered as compared to wild-type strains using specific anti-PIA and anti-20-kDaPS antisera. While periodate oxidation and dispersin B treatments abolish immuno-reactivity and intercellular adhesive properties of PIA, no abrogative activity is exerted towards 20-kDaPS immunochemical reactivity following these treatments. PIA polysaccharide I-containing fractions eluting from Q-Sepharose were devoid of detectable 20-kDaPS using specific ELISA. Preincubation of non-20-kDaPS-producing clinical strain with increasing amounts of 20-kDaPS inhibits endocytosis by human macrophages, whereas, preincubation of 20-kDaPS-producing strain ATCC35983 with 20-kDaPS antiserum enhances bacterial endocytosis by human macrophages. In conclusion, icaADBC is not involved in 20-kDaPS synthesis, while the chemical and chromatographic properties of PIA and 20-kDaPS are distinct. 20-kDaPS exhibits anti-phagocytic properties, whereas, 20-kDaPS antiserum may have a beneficial effect on combating infection by 20-kDaPS-producing S. epidermidis.


Deletion of the SSK1 response regulator gene in Candida albicans contributes to enhanced killing by human polymorphonuclear neutrophils.
The isolation and partial functional characterization of the two-component response regulator SSK1 gene of Candida albicans was previously reported. Compared to wild-type (CAF2-1) and gene-reconstituted (SSK23) strains, the ssk1 null strain (SSK21) was avirulent in a murine model of hematogenously disseminated candidiasis and less able to adhere to human esophageal cells. More recent data indicate that SSK21 is sensitive to 4 to 8 mM H(2)O(2) in vitro than CAF2-1 and SSK23. Furthermore, microarray studies indicate that the regulation of two classes of genes, those encoding cell wall functions and stress adaptation, are altered in the ssk1 mutant. In the present study, the susceptibility of strains CAF2-1, SSK21, and SSK23 to killing by human polymorphonuclear neutrophils (PMNs) was assessed. Results are also described for a newly constructed ssk1 mutant (SSK24) in which the URA3 gene is integrated into its native locus. Our results indicate that killing of SSK21 and SSK24 was significantly greater than that of CAF2-1 and SSK23 (P < 0.01). In order to determine why Ssk1p at least partially protects the organism against the killing activity of human PMNs, we compared the signal transduction activity and the inflammatory response gene profiles of PMNs infected with either the wild type or the ssk1 mutant. Phosphorylation of the mitogen-activated protein kinases p42/44 and p38 from neutrophils infected with either CAF2-1 (wild type) or SSK21 (ssk1/ssk1) was similar, while expression and phosphorylation of the JNK mitogen-activated protein kinase was not observed following infection with either strain. On the other hand, we observed an upregulation of seven inflammatory response genes in PMNs infected with the SSK21 mutant only, while an increase in interleukin-10 expression was measured in PMNs infected with either strain. Downregulation of interleukin-2 was observed in PMNs infected with either strain. Verification of the transcriptional profiling was obtained by reverse transcription-PCR for three of the genes that were upregulated in neutrophils infected with the ssk1 mutant. Also, the sensitivity of strain SSK21 to human defensin-1, one of the nonoxidative, antimicrobial peptides of PMNs, was greater than that of CAF2-1, demonstrating that nonoxidative killing in PMNs may contribute to the increased susceptibility of the ssk1 mutant. Our results indicate that the Ssk1p response regulator protein may provide at least partial adaptive functions for the survival of C. albicans following its encounter with human neutrophils.


Expression of tumor antigens on primary ovarian cancer cells compared to established ovarian cancer cell lines.
In order to select a suitable combination of cancer cell lines as an appropriate source of antigens for dendritic cell-based immunotherapy of ovarian cancer, we analyzed the expression level of 21 tumor associated antigens (BIRC5, CA125, CEA, DDX43, EPCAM, FOLR1, Her-2/neu, MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A10, MAGE-A12, MUC-1, NY-ESO-1, PRAME, p53, TPBG, TRT, WT1) in 4 established ovarian cancer cell lines and in primary tumor cells isolated from the high-grade serous epithelial ovarian cancer tissue. More than 90% of tumor samples expressed very high levels of CA125, FOLR1, EPCAM and MUC-1 and elevated levels of Her-2/neu, similarly to OVCAR-3 cell line. The combination of OV-90 and OVCAR-3 cell lines showed the highest overlap with patients' samples in the TAA expression profile.


Novel method for detection, typing, and quantification of human papillomaviruses in clinical samples.
We report the development of a novel detection and typing methodology for human papillomaviruses (HPV) based on real-time PCR with the self-probing fluorescent primers known as Scorpions. This technique is quick, simple, specific, sensitive, and capable of estimating viral load per cell. We report the results of over 100 typing reactions performed on cell lines, biopsies, and cervical cytobrush samples which, when compared to the current reference HPV detection and typing technique, present a kappa value of 0.89. We further report preliminary data suggesting a relationship between viral load per cell and grade of cervical disease.


Mipsagargin, a novel thapsigargin-based PSMA-activated prodrug: results of a first-in-man phase I clinical trial in patients with refractory, advanced or metastatic solid tumours.
Mipsagargin (G-202; (8-O-(12-aminododecanoyl)-8-O-debutanoyl thapsigargin)-Asp-γ-Glu-γ-Glu-γ-GluGluOH)) is a novel thapsigargin-based targeted prodrug that is activated by PSMA-mediated cleavage of an inert masking peptide. The active moiety is an inhibitor of the sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA) pump protein that is necessary for cellular viability. We evaluated the safety of mipsagargin in patients with advanced solid tumours and established a recommended phase II dosing (RP2D) regimen. Patients with advanced solid tumours received mipsagargin by intravenous infusion on days 1, 2 and 3 of 28-day cycles and were allowed to continue participation in the absence of disease progression or unacceptable toxicity. The dosing began at 1.2 mg m(-2) and was escalated using a modified Fibonacci schema to determine maximally tolerated dose (MTD) with an expansion cohort at the RP2D. Plasma was analysed for mipsagargin pharmacokinetics and response was assessed using RECIST criteria. A total of 44 patients were treated at doses ranging from 1.2 to 88 mg m(-2), including 28 patients in the dose escalation phase and 16 patients in an expansion cohort. One dose-limiting toxicity (DLT; Grade 3 rash) was observed in the dose escalation portion of the study. At 88 mg m(-2), observations of Grade 2 infusion-related reaction (IRR, 2 patients) and Grade 2 creatinine elevation (1 patient) led to declaration of 66.8 mg m(-2) as the recommended phase II dose (RP2D). Across the study, the most common treatment-related adverse events (AEs) were fatigue, rash, nausea, pyrexia and IRR. Two patients developed treatment-related Grade 3 acute renal failure that was reversible during the treatment-free portion of the cycle. To help ameliorate the IRR and creatinine elevations, a RP2D of 40 mg m(-2) on day 1 and 66.8 mg m(-2) on days 2 and 3 with prophylactic premedications and hydration on each day of infusion was established. Clinical response was not observed, but prolonged disease stabilisation was observed in a subset of patients. Mipsagargin demonstrated an acceptable tolerability and favourable pharmacokinetic profile in patients with solid tumours.


Molecular cloning, sequencing, and gene expression analysis of tributyltin-binding protein type 1 in Japanese medaka fish, Oryzias latipes.
The full-length cDNA sequence of tributyltin-binding protein type 1 in Japanese medaka (Oryzias latipes) (Olat.TBT-bp1) was determined by means of rapid amplification of cDNA ends (RACE) of liver tissue. Analysis of the structure of the gene encoding Olat.TBT-bp1 revealed that the exonintron organization of this gene corresponds to that of the genes encoding lipocalin superfamily proteins, suggesting that Olat.TBT-bp1 can be categorized as a member of the lipocalin superfamily, which may play an important role in transportation, detoxification, and excretion of xenobiotic compounds. Reverse transcription - PCR revealed that Olat.TBT-bp1 was expressed mainly in the liver, and upregulation of its expression was detected 1, 2, and 4 weeks post hatching. Relative expression of the Olat.TBT-bp1 gene was significantly downregulated, compared with that in the solvent control, by exposure to tributyltin at 0.01 mg/l or triclosan at 1.7 mg/l. Further studies on Olat.TBT-bp1 expression in conjunction with other biochemical and physiological toxicities in response to chemical exposures are needed to increase our understanding and information of TBT-bps mechanisms and as molecular biomarkers of chemical exposures. The role of Olat.TBT-bp1 in xenobiotic detoxification and/or excretion needs more investigations.


Human infection studies: Key considerations for challenge agent development and production.
Human infection (or challenge) studies involve the intentional administration of a pathogen (challenge agent) to volunteers. The selection, isolation, development and production of the challenge agent is one of the first steps in developing a challenge study and critical for minimising the risk to volunteers. Regulatory oversight for this production differs globally. Manufacturing agents within a Good Manufacturing Practice (GMP) facility reduces the risk of the manufacturing process by including processes such as confirming the identity of the challenge agent and ascertaining that it's pure and free from impurities. However, in some cases it's not possible or feasible to manufacture to GMP standards, for example where the challenge agent requires an intermediate vector for growth. There is lack of clear guidance on what the minimum requirements for high-quality safe manufacture outside of GMP facilities should be and here we describe the development of a considerations document for the selection and production of challenge agents to meet this need.


Organ allotransplantation since the advent of cyclosporin.
Successful long-term organ transplantation has been made possible by the use of conventional immunosuppression. In contrast with transplantation of other organs, transplantation of the kidney has become an accepted successful form of therapy, 80% of patients being fully rehabilitated. However, complications of therapy are frequent and severe and include bone necrosis, cataract formation, infections and stunted growth in children. The discovery of the immunosuppressive properties of cyclosporin A (CYA) by Borel in 1976 offered new hope to recipients of hepatic, cardiac, pancreatic and heart-lung transplants, since rejection frequently resulted in death. Although the use of CYA has led to significant accomplishments, subsequent studies have documented deleterious side-effects including nephrotoxicity, hepatotoxicity, hirsutism, gingival hyperplasia, tremors and tumours. Yet despite the side-effects, CYA has proved to be a promising immunosuppressive agent for use in human organ transplantation and is at present being evaluated in transplant centres throughout the world.


Analysis of apolipoprotein E nuclear localization using green fluorescent protein and biotinylation approaches.
Previous results indicate that apoE (apolipoprotein E) may be associated with the nucleus in specific cell types, particularly under stress conditions such as serum starvation. In addition, nuclear apoE localization in ovarian cancer was recently shown to be correlated with patient survival. In order to better understand the factors associated with apoE nuclear localization, we examined intracellular apoE trafficking using live-cell imaging of CHO (Chinese-hamster ovary) cells that constitutively expressed apoE-GFP (green fluorescent protein). In addition, we used biotinylated apoE (in a lipid-free state and as a lipidated discoidal complex) to track the uptake and potential nuclear targeting of exogenous apoE. Our results indicate that a small proportion of apoE-GFP is detected in the nucleus of living apoE-GFP-expressing CHO cells and that the level of apoE-GFP in the nucleus is increased with serum starvation. Exposure of control CHO cells to exogenous apoE-GFP did not result in nuclear apoE-GFP localization in the recipient cells. Similarly, biotinylated apoE did not reach the nucleus of control CHO cells or SK-N-SH neurons. In contrast, when biotinylated apoE was delivered to recipient cells as a lipidated apoE disc, apoE was detected in the nucleus, suggesting that the lipoprotein complex alters the intracellular degradation or trafficking of apoE. Biotinylated apoE discs containing each of the three common human apoE isoforms (E2, E3 and E4) were also tested for nuclear trafficking. All three apoE isoforms were equally detected in the nucleus. These studies provide new evidence that apoE may be targeted to the nucleus and shed light on factors that regulate this process.


Prevalence of cardiovascular disease risk factors among a Nigerian adult population: relationship with income level and accessibility to CVD risks screening.
In Nigeria, reports on the prevalence of modifiable cardiovascular disease (CVD) risk factors are scarce. In addition, socio-economic status (SES), an important component of the socioeconomic gradient in CVD and its risk factors has not been clearly elucidated. This study sought to assess the prevalence of CVD risk factors and how the difference in prevalence and accessibility to CVD risk screening across income levels and educational backgrounds contributes to disease diagnosis in rural and urban Nigerian adults. A cross sectional study was carried out on a sociocultural ethnic group of persons living in rural and urban settings. All participants were aged ≥ 18 years. The WHO STEPS questionnaire was used to document the demographics, history of previous medical check-up or screening, anthropometric and biochemical measurements of the participants. Average income level and educational status were indicators used to assess the impact of SES. Multivariate analyses were performed to assess any difference between the geographical locations and SES indicators, and prevalence of CVD risk factors and access to CVD risk screening. The 422 participants (273 females and 149 males) [corrected] had mean age (± standard deviation) of 38.3 ± 20.5 and 42.9 ± 20.7 years, respectively. Only total cholesterol (p = 0.001), triglyceride (p = 0.005), high density lipoprotein cholesterol (HDL) (p < 0.0001), body mass index (BMI) (p = 0.03) and average income rate (p = 0.01) showed significant difference between gender groups. Overall prevalence of prediabetes (4.9%), diabetes (5.4%), hypertension (35.7%), low HDL (17.8%), hypertriglyceridemia (23.2%), hypercholesterolemia (38.1%) and central obesity of 52.2% was recorded. Except between total cholesterol (p = 0.042) and HDL (p = 0.017), other CVD risk factors did not show a statistical significance across income levels. Participants with 'university and postgraduate education' had higher access to blood pressure and blood glucose screening compared to other educational groups; and this showed a statistical significance. This study has shown that a significant number of modifiable CVD risk factors exist in the rural and urban migrants of an adult Nigerian population. While income level did not affect the CVD risk factor prevalence, it did affect accessibility to CVD risk screening. There is a need for access to diagnosis of modifiable risk factors at all levels of society.


Phenological synchronization drives demographic rates of populations.
Phenology is increasingly recognized as an important factor structuring communities because it determines when and at what life stage organisms interact. Previous work indicates that changes in first or mean timing of a phenological event can affect populations and communities, but little is known about the consequences of changes in the distribution (e.g., synchrony) of a phenological event. We conducted an experiment using an anuran study system to determine how synchrony of reproduction and egg hatching affects offspring performance, whether the effects are density dependent, and how hatching synchrony influences the synchrony of a subsequent phenological event (metamorphosis). Changes in hatching synchrony altered survival, development rates, and body size at metamorphosis, which can affect post-metamorphosis performance. The degree of synchrony at hatching also affected the degree of synchrony at metamorphosis, indicating that timing of one stage can carry over to affect that of later ones. Importantly, these effects were all density dependent, likely because decreasing hatching synchrony switched intraspecific interactions from scramble to contest competition. This study demonstrates that phenological synchrony has important consequences for ecological interactions and population dynamics, emphasizing the need to develop a comprehensive understanding of how shifts in phenological distributions affect communities.


Bacterial colonization with balloon uterine stent placement in the uterus for 30 days: a randomized controlled clinical trial.
To assess bacterial colonization following balloon uterine stent placement in the uterus for 30 days. Prospective randomized controlled study. Tertiary medical center. Sixty-eight women scheduled for hysteroscopy. Women who were undergoing hysteroscopic surgery were randomly assigned to receive a balloon uterine stent or not. Before starting surgery, the uterine cavity was swabbed for bacterial culture. The device was placed in the uterus after surgery in the stent group. After 30 days, the stent was removed and sent for culture and the uterine cavity also swabbed and cultured. The uterine cavities of the control patients were swabbed before and 30 days after surgery. The primary outcome was the incidence of bacterial colonization of the uterus. Secondary outcomes were pain intensity and species of colonizing bacteria. Excluding eight women, 30 women in each group were included in this analysis. In the stent group, three women (10.0%) demonstrated bacterial colonization before surgery compared with nine women (30.0%) after 30 days. In the control group, four (13.3%) and ten (33.3%) women had microorganisms detected in the uterus before and after 30 days after surgery, respectively. In neither group did the percentage of women with uterine microorganisms increase significantly after 30 days. The percentages of women with uterine bacterial colonization before and 30 days after surgery were similar between both groups. Balloon uterine stents may be placed after surgery for up to 30 days without increasing bacterial colonization. ClinicalTrials.gov (www.clinicaltrials.gov) NCT01167296.


An Evaluation of the Family Informal Caregiver Stroke Self-Management Program.
Caregivers are often unprepared and overwhelmed with the responsibilities of providing care to stroke survivors, which can lead to negative physical and psychological effects. To evaluate the impact of the Family Informal Caregiver Stroke Self-Management (FICSS) program on burden and life changes resulting from providing care among family caregivers of stroke survivors. A prospective pre-test and post-test design using quantitative and qualitative data was used to evaluate the program with a convenience sample of 42 caregivers. The four-module facilitated program consisted of small group-guided discussion. Quantitative evaluations were completed at baseline, 2 weeks and 6 months (post-intervention), and qualitative data were collected at 2 weeks and 6 months. Life changes and burden were measured using the Bakas Caregiving Outcome Scale (BCOS) and the Oberst Caregiving Burden Scale (OCBS), respectively. The BCOS scores increased consistently over time, showing significant differences at 6 months compared with 2 weeks (mean difference: 5.29, 95% confidence interval [CI]: 0.30-10.28, p=0.04) and baseline (mean difference: 7.58, 95% CI: 2.92-12.23, p=0.001). The OCBS time scores decreased consistently over time, showing a significant difference at 6 months compared with baseline (mean difference: -5.20, 95% CI: -0.96 to -9.44, p=0.02). The OCBS difficulty scores fluctuated over time, resulting in no overall difference from baseline to 6 months. Qualitative themes were consistent with the positive quantitative findings. Study results suggest that the FICSS program may result in reduced caregiver burden and improved life changes resulting from providing care.


Killer immunoglobulin-like receptor gene repertoire influences viral load of primary human cytomegalovirus infection in renal transplant patients.
Killer cell immunoglobulin-like receptors (KIR) are highly polymorphic members of the immunoglobulin superfamily, which influence the response of natural killer cells and some T-lymphocyte subsets. Analysis of a cohort of previously human cytomegalovirus (HCMV)-negative patients, who developed primary HCMV infection following HCMV-positive renal transplant (n=76), revealed an increase in the frequency of KIR genes located on the telomeric region of B haplotypes (Tel B). The presence of Tel B in combination with the KIR ligand HLA-C2 was significantly more frequent in this subgroup. These genetic factors were associated with resistance to HCMV infection in a second cohort (n=65), where the Tel B genes KIR2DL5, -2DS1, 2DS5 and -3DS1 were all significantly associated with high viral loads. Furthermore, the KIR haplotype Tel A when in combination with the KIR ligand HLA-C1 was significantly protective against the development of severe infection. Our results suggest that KIR are a significant factor in the control of primary HCMV infection, and that determination of KIR gene repertoire may help in detection of renal transplant patients who were most at risk.


Increasing mode instability thresholds of fiber amplifiers by gain saturation.
We show by numerical modeling that saturation of the population inversion reduces the stimulated thermal Rayleigh gain relative to the laser gain in large mode area fiber amplifiers. We show how to exploit this effect to raise mode instability thresholds by a substantial factor. We also demonstrate that when suppression of stimulated Brillouin scattering and the population saturation effect are both taken into account, counter-pumped amplifiers have higher mode instability thresholds than co-pumped amplifiers for fully Yb3+ doped cores, and confined doping can further raise the thresholds.


Complex genetic control of HDL levels in mice in response to an atherogenic diet. Coordinate regulation of HDL levels and bile acid metabolism.
Inbred strains of mice differ in susceptibility to atherogenesis when challenged with a high fat, high cholesterol diet containing 0.5% cholic acid. Studies of recombinant inbred (RI) strains derived from the susceptible strain C57BL/6J (B6) and the resistant strains C3H/HeJ (C3H) and BALB/cJ have revealed an association between fatty streak lesion size and a decrease in high density lipoprotein (HDL) levels on the diet. To better understand the genetic factors contributing to HDL metabolism and atherogenesis in response to the diet, we studied mice derived from an intercross between B6 and C3H using a complete linkage map approach. A total of 185 female progeny were typed for 134 genetic markers spanning the mouse genome, resulting in an average interval of about 10 cM between markers. A locus on distal chromosome 1 containing the apolipoprotein AII gene was linked to HDL-cholesterol levels on both the chow and the atherogenic diets, but this locus did not contribute to the decrease in HDL-cholesterol in response to the diet. At least three distinct genetic loci, on chromosomes 3, 5, and 11, exhibited evidence of linkage to a decrease in HDL-cholesterol after a dietary challenge. Since a bile acid (cholic acid) is required for the diet induced changes in HDL levels and for atherogenesis in these strains, we examined cholesterol-7-alpha hydroxylase (C7AH) expression. Whereas B6 mice exhibited a large decrease in C7AH mRNA levels in response to the diet, C3H showed an increase. Among the intercross mice, multiple loci contributed to the regulation of C7AH mRNA levels in response to the diet, the most notable of which coincided with the loci on chromosomes 3, 5, and 11 controlling HDL levels in response to the diet. None of these loci were linked to the C7AH structural gene which we mapped to proximal chromosome 4. These studies reveal coordinate regulation of C7AH expression and HDL levels, and they indicate that the genetic factors controlling HDL levels are more complex than previously suggested by studies of RI strains. Furthermore, we observed that two of the loci for C7AH expression contributed to differences in gallstone formation between these strains.


Hepatitis associated with prothionamide for treatment of multidrug-resistant tuberculosis.
Timely and intensive monitoring for, and management of, adverse effects caused by anti-tuberculosis drugs are essential components of control programs for multidrug-resistant tuberculosis (MDR-TB). This retrospective case series was conducted in northern Taiwan from January 2007 to December 2008 at Taipei Medical University-Wan Fang Hospital, a 750-bed tertiary-care center and MDR-TB referral center. Hepatitis associated with prothionamide was defined as the recurrence of hepatitis after a second prothionamide treatment re-challenge. In total, 47 patients with MDR-TB enrolled in the Directly Observed Therapy, Short Course-Plus Program were identified during the study period, and 44 (93.6%) were treated with prothionamide. Seven of these 44 patients (15.9%) developed hepatitis after being treated with prothionamide concurrent with other anti-tuberculosis agents. Hepatitis associated with prothionamide occurred in three of these seven patients (6.8%). In these three patients, hepatitis developed following treatment with prothionamide for 28 days, 39 days or 45 days. Hepatitis developed rapidly after re-challenge with prothionamide at 4 days, 4 days and 3 days, respectively. Liver function returned to the normal range after cessation of prothionamide treatment for 19 days, 27 days or 28 days. Close monitoring of liver function was necessary in MDR-TB patients who received prothionamide treatment.


Clostridium difficile exposure as an insidious source of infection in healthcare settings: an epidemiological model.
Clostridium difficile is the leading cause of infectious diarrhea in hospitalized patients. Its epidemiology has shifted in recent years from almost exclusively infecting elderly patients in whom the gut microbiota has been disturbed by antimicrobials, to now also infecting individuals of all age groups with no recent antimicrobial use. A stochastic mathematical model was constructed to simulate the modern epidemiology of C. difficile in a healthcare setting, and, to compare the efficacies of interventions. Both the rate of colonization and the incidence of symptomatic disease in hospital inpatients were insensitive to antimicrobial stewardship and to the prescription of probiotics to expedite healthy gut microbiota recovery, suggesting these to be ineffective interventions to limit transmission. Comparatively, improving hygiene and sanitation and reducing average length of stay more effectively reduced infection rates. Although the majority of new colonization events are a result of within-hospital ward exposure, simulations demonstrate the importance of imported cases with new admissions. By analyzing a wide range of screening sensitivities, we identify a previously ignored source of pathogen importation: although capturing all asymptomatic as well as symptomatic introductions, individuals who are exposed but not yet colonized will be missed by even a perfectly sensitive screen on admission. Empirical studies to measure the duration of this latent period of infection will be critical to assessing C. difficile control strategies. Moreover, identifying the extent to which the exposed category of individual contributes to pathogen importation should be explicitly considered for all infections relevant to healthcare settings.


Attachment, culture, and gene-culture co-evolution: expanding the evolutionary toolbox of attachment theory.
I argue that attachment relationships, and particularly secure ones, are important contexts for social learning and cultural transmission. Bowlby originally treated the attachment-behavioral system as serving only one evolutionary function: protection, via physical proximity. Yet the time is ripe to consider learning, especially social learning, as an additional functional consequence of attachment. Updated accordingly, attachment theory has the potential to serve as a much-needed developmental anchor for models of cultural evolution and gene-culture co-evolution. To support my arguments, I review progress in evolutionary science since Bowlby's lifetime, highlighting the growing recognition of ecological flexibility and the cultural embeddedness of animal behavior. I also review research pointing to a facilitating role of secure attachment relationships for social learning from caregivers among humans. For illustrational purposes, I show how one important aspect of human culture - religion - is culturally transmitted within attachment relationships, and of how the generalization of attachment-related working models biases the cultural transmission of religion from parents to offspring. I end the paper with a call for empirical research to test the role of attachment in cultural transmission beyond religion.


Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society.
To update the evidence-based position statement published by The North American Menopause Society (NAMS) in 2006 regarding the management of osteoporosis in postmenopausal women. NAMS followed the general principles established for evidence-based guidelines to create this updated document. A panel of clinicians and researchers expert in the field of metabolic bone diseases and/or women's health was enlisted to review the 2006 NAMS position statement, compile supporting statements, and reach consensus on recommendations. The panel's recommendations were reviewed and approved by the NAMS Board of Trustees. Osteoporosis, which is especially prevalent among older postmenopausal women, increases the risk of fractures. Hip and spine fractures are associated with particularly high morbidity and mortality in this population. Given the health implications of osteoporotic fractures, the primary goal of osteoporosis therapy is to prevent fractures, which is accomplished by slowing or stopping bone loss, maintaining bone strength, and minimizing or eliminating factors that may contribute to fractures. The evaluation of postmenopausal women for osteoporosis risk requires a medical history, physical examination, and diagnostic tests. Major risk factors for postmenopausal osteoporosis (as defined by bone mineral density) include advanced age, genetics, lifestyle factors (such as low calcium and vitamin D intake, smoking), thinness, and menopause status. The most common risk factors for osteoporotic fracture are advanced age, low bone mineral density, and previous fracture as an adult. Management focuses first on nonpharmacologic measures, such as a balanced diet, adequate calcium and vitamin D intake, adequate exercise, smoking cessation, avoidance of excessive alcohol intake, and fall prevention. If pharmacologic therapy is indicated, government-approved options are bisphosphonates, selective estrogen-receptor modulators, parathyroid hormone, estrogens, and calcitonin. Management strategies for postmenopausal women involve identifying those at risk for fracture, followed by instituting measures that focus on reducing modifiable risk factors through dietary and lifestyle changes and, if indicated, pharmacologic therapy.


Single-turnover and steady-state kinetics of hydrolysis of cephalosporins by beta-lactamase I from Bacillus cereus.
The kinetics of the hydrolysis of two cephalosporins by beta-lactamase I from Bacillus cereus 569/H/9 has been studied by single-turnover and steady-state methods. Single-turnover kinetics could be measured over the time scale of minutes when cephalosporin C was the substrate. The other substrate, 7-(2',4'-dinitrophenylamino)deacetoxycephalosporanic acid, was hydrolysed even more slowly, and has potential for use in crystallographic studies of beta-lactamases. Comparison of single-turnover and steady-state kinetics showed that, for both substrates, opening the beta-lactam ring (i.e. acylation of the enzyme) was the rate-determining step. Thus the non-covalent enzyme-substrate complex is expected to be the intermediate observed crystallographically.


Visual deficits in anisometropia.
Amblyopia is usually associated with the presence of anisometropia, strabismus or both early in life. We set out to explore quantitative relationships between the degree of anisometropia and the loss of visual function, and to examine how the presence of strabismus affects visual function in observers with anisometropia. We measured optotype acuity, Pelli-Robson contrast sensitivity and stereoacuity in 84 persons with anisometropia and compared their results with those of 27 persons with high bilateral refractive error (isoametropia) and 101 persons with both strabismus and anisometropia. All subjects participated in a large-scale study of amblyopia (McKee et al., 2003). We found no consistent visual abnormalities in the strong eye, and therefore report only on vision in the weaker, defined as the eye with lower acuity. LogMAR acuity falls off markedly with increasing anisometropia in non-strabismic anisometropes, while contrast sensitivity is much less affected. Acuity degrades rapidly with increases in both hyperopic and myopic anisometropia, but the risk of amblyopia is about twice as great in hyperopic than myopic anisometropes of comparable refractive imbalance. For a given degree of refractive imbalance, strabismic anisometropes perform considerably worse than anisometropes without strabismus--visual acuity for strabismics was on average 2.5 times worse than for non-strabismics with similar anisometropia. For observers with equal refractive error in the two eyes there is very little change in acuity or sensitivity with increasing (bilateral) refractive error except for one extreme individual (bilaterally refractive error of -15 D). Most pure anisometropes with interocular differences less than 4D retain some stereopsis, and the degree is correlated with the acuity of the weak eye. We conclude that even modest interocular differences in refractive error can influence visual function.


The epidemiology of respiratory syncytial virus lower respiratory tract infections in children less than 5 years of age in Indonesia.
Although the epidemiology of respiratory syncytial virus (RSV) lower respiratory tract infections (LRI) is well known in industrialized countries, the burden in developing Asian countries is not well studied. To define the burden of RSV disease in children <5 years of age in rural and urban Indonesia, infants and children were enrolled from peri-urban and rural subdistricts, in the following 2 cohorts: (a) a cross-sectional cohort of approximately 100 children from each of 2 subdistricts in the following 5 age groups: 3 to 5, 6 to 8, 9 to 11, 12 to 23, and 24 to 48 months; (b) a birth cohort of all newborns in both subdistricts during the 28 months of the study. All subjects were visited weekly at home. Children with World Health Organization-defined LRI or wheezing had a nasal wash for detection of RSV using an enzyme immunoassay and polymerase chain reaction. Of the 2014 children studied, 1074 were in the cross-sectional and 940 in the newborn cohorts. Of the 802 episodes of LRI, 163 were caused by RSV. The RSV LRI incidence per 1000 child-years (C-Y) was higher in rural areas (57.25 vs. 38.54), P < 0.05. No RSV LRI occurred in the first 2 months of life and the peak incidence was in the 6- to 8-month-old infants (103/1000 C-Y). The rates were lowest in those <6 months, 16.5 per 1000 C-Y, compared with 83.1 per 1000 C-Y in those 6 to 11 months of age (P < 0.001), 66.99 in those 12 to 23 months of age, and 28.1 in 2- to 5-year-olds. In Indonesia, the incidence of RSV LRI in the first 6 months of life is relatively low with most disease occurring in older children.


Does delivery volume of family physicians predict maternal and newborn outcome?
The number of births attended by individual family physicians who practice intrapartum care varies. We wanted to determine if the practice-volume relations that have been shown in other fields of medical practice also exist in maternity care practice by family doctors. For the period April 1997 to August 1998, we analyzed all singleton births at a major maternity teaching hospital for which the family physician was the responsible physician. Physicians were grouped into 3 categories on the basis of the number of births they attended each year: fewer than 12, 12 to 24, and 25 or more. Physicians with a low volume of deliveries (72 physicians, 549 births), those with a medium volume of deliveries (34 physicians, 871 births) and those with a high volume of deliveries (46 physicians, 3024 births) were compared in terms of maternal and newborn outcomes. The main outcome measures were maternal morbidity, 5-minute Apgar score and admission of the baby to the neonatal intensive care unit or special care unit. Secondary outcomes were obstetric procedures and consultation patterns. There was no difference among the 3 volume cohorts in terms of rates of maternal complications of delivery, 5-minute Apgar scores of less than 7 or admissions to the neonatal intensive care unit or the special care unit, either before or after adjustment for parity, pregnancy-induced hypertension, diabetes, ethnicity, lone parent status, maternal age, gestational age, newborn birth weight and newborn head circumference at birth. High- and medium-volume family physicians consulted with obstetricians less often than low-volume family physicians (adjusted odds ratio [OR] 0.586 [95% confidence interval, CI, 0.479-0.718] and 0.739 [95% CI 0.583-0.935] respectively). High- and medium-volume family physicians transferred the delivery to an obstetrician less often than low-volume family physicians (adjusted OR 0.668 [95% CI 0.542-0.823] and 0.776 [95% CI 0.607-0.992] respectively). Inductions were performed by medium-volume family physicians more often than by low-volume family physicians (adjusted OR 1.437 [95% CI 1.036-1.992]. Family physicians' delivery volumes were not associated with adverse outcomes for mothers or newborns. Low-volume family physicians referred patients and transferred deliveries to obstetricians more frequently than high- or medium-volume family physicians. Further research is needed to validate these findings in smaller facilities, both urban and rural.


The association of a SNP upstream of INSIG2 with body mass index is reproduced in several but not all cohorts.
A SNP upstream of the INSIG2 gene, rs7566605, was recently found to be associated with obesity as measured by body mass index (BMI) by Herbert and colleagues. The association between increased BMI and homozygosity for the minor allele was first observed in data from a genome-wide association scan of 86,604 SNPs in 923 related individuals from the Framingham Heart Study offspring cohort. The association was reproduced in four additional cohorts, but was not seen in a fifth cohort. To further assess the general reproducibility of this association, we genotyped rs7566605 in nine large cohorts from eight populations across multiple ethnicities (total n = 16,969). We tested this variant for association with BMI in each sample under a recessive model using family-based, population-based, and case-control designs. We observed a significant (p < 0.05) association in five cohorts but saw no association in three other cohorts. There was variability in the strength of association evidence across examination cycles in longitudinal data from unrelated individuals in the Framingham Heart Study Offspring cohort. A combined analysis revealed significant independent validation of this association in both unrelated (p = 0.046) and family-based (p = 0.004) samples. The estimated risk conferred by this allele is small, and could easily be masked by small sample size, population stratification, or other confounders. These validation studies suggest that the original association is less likely to be spurious, but the failure to observe an association in every data set suggests that the effect of SNP rs7566605 on BMI may be heterogeneous across population samples.


Cerebrospinal fluid monoamine metabolites, aggression, and impulsivity in disruptive behavior disorders of children and adolescents.
Cerebrospinal fluid levels of 5-hydroxyindoleacetic acid, a metabolite of serotonin, were measured in relation to aggression, impulsivity, and social functioning in 29 children and adolescents with disruptive behavior disorders. The cerebrospinal fluid 5-hydroxyindoleacetic acid level was low compared with that of age-, sex-, and race-matched patients with obsessive-compulsive disorder. Within the disruptive group, significant negative correlations with age-corrected 5-hydroxyindoleacetic acid level were seen for the child's report of aggression toward people and the expressed emotionality of the child toward his or her mother; other correlations of age-corrected 5-hydroxyindoleacetic acid level with measures of aggression were in the expected negative direction but did not reach statistical significance. Impulsivity per se and socioenvironmental factors were not significantly related to cerebrospinal fluid 5-hydroxyindoleacetic acid concentration.


Upgrading a microplate reader for photobiology and all-optical experiments.
Automation can vastly reduce the cost of experimental labor and thus facilitate high experimental throughput, but little off-the-shelf hardware for the automation of illumination experiments is commercially available. Here, we use inexpensive open-source electronics to add programmable illumination capabilities to a multimode microplate reader. We deploy this setup to characterize light-triggered phenomena in three different sensory photoreceptors. First, we study the photoactivation of Arabidopsis thaliana phytochrome B by light of different wavelengths. Second, we investigate the dark-state recovery kinetics of the Synechocystis sp. blue-light sensor Slr1694 at multiple temperatures and imidazole concentrations; while the kinetics of the W91F mutant of Slr1694 are strongly accelerated by imidazole, the wild-type protein is hardly affected. Third, we determine the light response of the Beggiatoa sp. photoactivatable adenylate cyclase bPAC in Chinese hamster ovary cells. bPAC is activated by blue light in dose-dependent manner with a half-maximal intensity of 0.58 mW cm(-2); intracellular cAMP spikes generated upon bPAC activation decay with a half time of about 5 minutes after light switch-off. Taken together, we present a setup which is easily assembled and which thus offers a facile approach to conducting illumination experiments at high throughput, reproducibility and fidelity.


Atypical Crouzon syndrome with a novel Cys62Arg mutation in FGFR2 presenting with sagittal synostosis.
The management of a 1-year-old boy with Crouzonoid features is presented with a description of molecular genetic investigations that revealed a previously unreported mutation of the fibroblast growth factor receptor 2 (FGFR2) gene encoding the amino acid substitution p.Cys62Arg within the immunoglobin-like (IgI) domain. The patient presented in atypical fashion with severe sagittal synostosis but only mild exorbitism and hypertelorism. Owing to the progressively increasing size of the cranial occipital bullet, a total calvarial modeling procedure was performed at 8 months of age to correct the craniofacial deformity. Standard genetic testing of the major mutational "hotspots" associated with craniosynostosis was initially negative. However, further testing for atypical sites of mutation revealed a heterozygous nucleotide substitution (c.184T>C) in exon 3 of FGFR2. This mutation has not been previously reported and is only the second to be identified in the IgI domain; it was not present in either parent, indicating that it had arisen de novo. The child remains well 6 months postoperatively but will be monitored more closely compared with the usual protocol for nonsyndromic sagittal synostosis owing to the potential for increased risk of secondary complications. Key learning points from this case include the need for careful phenotypic evaluation of children presenting with apparently isolated sagittal synostosis and genetic testing for atypical mutations if the usual hotspots are negative.


Thyroxin treatment protects against white matter injury in the immature brain via brain-derived neurotrophic factor.
Low level of thyroid hormone is a strong independent risk factor for white matter (WM) injury, a major cause of cerebral palsy, in preterm infants. Thyroxin upregulates brain-derived neurotrophic factor during development. We hypothesized that thyroxin protected against preoligodendrocyte apoptosis and WM injury in the immature brain via upregulation of brain-derived neurotrophic factor. Postpartum (P) day-7 male rat pups were exposed to hypoxic ischemia (HI) and intraperitoneally injected with thyroxin (T4; 0.2 mg/kg or 1 mg/kg) or normal saline immediately after HI at P9 and P11. WM damage was analyzed for myelin formation, axonal injury, astrogliosis, and preoligodendrocyte apoptosis. Neurotrophic factor expression was assessed by real-time polymerase chain reaction and immunohistochemistry. Neuromotor functions were measured using open-field locomotion (P11 and P21), inclined plane climbing (P11), and beam walking (P21). Intracerebroventricular injection of TrkB-Fc or systemic administration of 7,8-dihydroxyflavone was performed. On P11, the HI group had significantly lower blood T4 levels than the controls. The HI group showed ventriculomegaly and marked reduction of myelin basic protein immunoreactivities in the WM. T4 (1 mg/kg) treatment after HI markedly attenuated axonal injury, astrocytosis, and microgliosis, and increased preoligodendrocyte survival. In addition, T4 treatment significantly increased myelination and selectively upregulated brain-derived neurotrophic factor expression in the WM, and improved neuromotor deficits after HI. The protective effect of T4 on WM myelination and neuromotor performance after HI was significantly attenuated by TrkB-Fc. Systemic 7,8-dihydroxyflavone treatment ameliorated hypomyelination after HI injury. T4 protects against WM injury at both pathological and functional levels via upregulation of brain-derived neurotrophic factor-TrkB signaling in the immature brain.


Hepatocellular carcinoma tumor board: making sense of the technologies.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death, with a rising global incidence. The vast majority of HCC cases occur in the setting of liver cirrhosis, mainly due to chronic hepatitis C (HCV) or hepatitis B (HBV) viral infections, alcohol consumption, and nonalcoholic fatty liver disease. The new approval of curative therapy with two NS5A inhibitors, ledipasvir and sofosbuvir, for the treatment of HCV will no doubt affect HCC incidence and outcome. No studies have evaluated the use of the new antivirals in patients with HCC. Staging and scoring remain an integral part of the management of patients with advanced HCC. Curative therapies for the treatment of HCC are evolving. Improvements in surgical techniques and risk stratification for orthotopic liver transplantation (OLT) have expanded access and improved the outlook for patients suffering from HCC. Interventional locoregional treatments continue to play a key role in the management of HCC. Transarterial chemoembolization is considered the standard of care for patients with noninvasive multinodular tumors at the intermediate stage. Bland embolization appears to have similar virtues in some studies. Y90 radioembolization represents a promising treatment option for patients unfit or refractory to transarterial chemoembolization. The advent of sorafenib as a standard of care with an improvement in survival sadly remain the only major breakthrough in the treatment of advanced HCC, with mounting negative data from multiple clinical trials. Advances in immunotherapy and customized therapy may hopefully help reverse this tide.


Outlier identification in radiation therapy knowledge-based planning: A study of pelvic cases.
The purpose of this study was to apply statistical metrics to identify outliers and to investigate the impact of outliers on knowledge-based planning in radiation therapy of pelvic cases. We also aimed to develop a systematic workflow for identifying and analyzing geometric and dosimetric outliers. Four groups (G1-G4) of pelvic plans were sampled in this study. These include the following three groups of clinical IMRT cases: G1 (37 prostate cases), G2 (37 prostate plus lymph node cases) and G3 (37 prostate bed cases). Cases in G4 were planned in accordance with dynamic-arc radiation therapy procedure and include 10 prostate cases in addition to those from G1. The workflow was separated into two parts: 1. identifying geometric outliers, assessing outlier impact, and outlier cleaning; 2. identifying dosimetric outliers, assessing outlier impact, and outlier cleaning. G2 and G3 were used to analyze the effects of geometric outliers (first experiment outlined below) while G1 and G4 were used to analyze the effects of dosimetric outliers (second experiment outlined below). A baseline model was trained by regarding all G2 cases as inliers. G3 cases were then individually added to the baseline model as geometric outliers. The impact on the model was assessed by comparing leverages of inliers (G2) and outliers (G3). A receiver-operating-characteristic (ROC) analysis was performed to determine the optimal threshold. The experiment was repeated by training the baseline model with all G3 cases as inliers and perturbing the model with G2 cases as outliers. A separate baseline model was trained with 32 G1 cases. Each G4 case (dosimetric outlier) was subsequently added to perturb the model. Predictions of dose-volume histograms (DVHs) were made using these perturbed models for the remaining 5 G1 cases. A Weighted Sum of Absolute Residuals (WSAR) was used to evaluate the impact of the dosimetric outliers. The leverage of inliers and outliers was significantly different. The Area-Under-Curve (AUC) for differentiating G2 (outliers) from G3 (inliers) was 0.98 (threshold: 0.27) for the bladder and 0.81 (threshold: 0.11) for the rectum. For differentiating G3 (outlier) from G2 (inlier), the AUC (threshold) was 0.86 (0.11) for the bladder and 0.71 (0.11) for the rectum. Significant increase in WSAR was observed in the model with 3 dosimetric outliers for the bladder (P < 0.005 with Bonferroni correction), and in the model with only 1 dosimetric outlier for the rectum (P < 0.005). We established a systematic workflow for identifying and analyzing geometric and dosimetric outliers, and investigated statistical metrics for outlier detection. Results validated the necessity for outlier detection and clean-up to enhance model quality in clinical practice.


Gastric emptying and plasma deuterium accumulation following ingestion of water and two carbohydrate-electrolyte beverages.
The purpose of this study was to compare the gastric emptying rates (GER) of water, a 6% carbohydrate (CHO) beverage, and a 20% CHO beverage and to contrast those rates against the rate at which deuterium oxide in the drinks accumulated in plasma (DAR) following beverage ingestion. Ten subjects (8 males, 2 females) cycled at 60% VO2max for 70 min; at 13 min, the subjects ingested 400 ml of one of the beverages. The GER and DAR of water and 6% CHO were similar, while GER and DAR were both significantly slowed by ingestion of 20% CHO. Although there was a significant correlation (r = .63, p < .05) between GER and DAR, only 40% of the variation in DAR could be accounted for by variation in GER. These data support the contention that DAR is partially determined by GER, with differences in the rate of fluid absorption across the intestine and other factors accounting for the remaining variation in DAR.


Mammographic texture synthesis: second-generation clustered lumpy backgrounds using a genetic algorithm.
Synthetic yet realistic images are valuable for many applications in visual sciences and medical imaging. Typically, investigators develop algorithms and adjust their parameters to generate images that are visually similar to real images. In this study, we used a genetic algorithm and an objective, statistical similarity measure to optimize a particular texture generation algorithm, the clustered lumpy backgrounds (CLB) technique, and synthesize images mimicking real mammograms textures. We combined this approach with psychophysical experiments involving the judgment of radiologists, who were asked to qualify the visual realism of the images. Both objective and psychophysical approaches show that the optimized versions are significantly more realistic than the previous CLB model. Anatomical structures are well reproduced, and arbitrary large databases of mammographic texture with visual and statistical realism can be generated. Potential applications include detection experiments, where large amounts of statistically traceable yet realistic images are needed.


Acupuncture for irritable bowel syndrome: a blinded placebo-controlled trial.
Irritable bowel syndrome (IBS) is a common disorder and many patients fail to find adequate relief from conventional therapies for their symptoms. This study tests the claim that acupuncture is effective for a majority of these patients. A prospective, blinded, sham acupuncture-controlled trial of traditional Chinese acupuncture was performed at a single postgraduate teaching hospital in Europe. Sixty patients with well-established IBS were recruited. The blinded comparator was sham acupuncture administered by the second of two acupuncturists who alone was aware of the randomization, and who otherwise followed the prescription of the first. The primary end-point was a defined fall in the symptom score at 13 wk (by intention to treat). The prior expectation was a 30% placebo response, and a response rate of 70% from acupuncture, for which the study was adequately powered. Patients in treated and sham groups improved significantly during the study-mean improvement in scores being equal (minus 1.9) and significant for both (P<0.05; one-tailed t test). There was a small numeric but non-significant difference between the response rate in patients receiving acupuncture (40.7%) and sham treatment (31.2%). Several secondary end-points marginally favored active treatment, but an improved symptom score of any degree of magnitude occurred more often with sham therapy (65.6% vs 59.2%). For no criterion was statistical significance approached. Traditional Chinese acupuncture is relatively ineffective in IBS in the European hospital setting, and the magnitude of any effect appears insufficient to warrant investment in acupuncture services.


Bioprinted 3D Primary Human Intestinal Tissues Model Aspects of Native Physiology and ADME/Tox Functions.
The human intestinal mucosa is a critical site for absorption, distribution, metabolism, and excretion (ADME)/Tox studies in drug development and is difficult to recapitulate in vitro. Using bioprinting, we generated three-dimensional (3D) intestinal tissue composed of human primary intestinal epithelial cells and myofibroblasts with architecture and function to model the native intestine. The 3D intestinal tissue demonstrates a polarized epithelium with tight junctions and specialized epithelial cell types and expresses functional and inducible CYP450 enzymes. The 3D intestinal tissues develop physiological barrier function, distinguish between high- and low-permeability compounds, and have functional P-gp and BCRP transporters. Biochemical and histological characterization demonstrate that 3D intestinal tissues can generate an injury response to compound-induced toxicity and inflammation. This model is compatible with existing preclinical assays and may be implemented as an additional bridge to clinical trials by enhancing safety and efficacy prediction in drug development.


The role of gene flow and chromosomal instability in shaping the bread wheat genome.
Bread wheat (Triticum aestivum) is one of the world's most important crops; however, a low level of genetic diversity within commercial breeding accessions can significantly limit breeding potential. In contrast, wheat relatives exhibit considerable genetic variation and so potentially provide a valuable source of novel alleles for use in breeding new cultivars. Historically, gene flow between wheat and its relatives may have contributed novel alleles to the bread wheat pangenome. To assess the contribution made by wheat relatives to genetic diversity in bread wheat, we used markers based on single nucleotide polymorphisms to compare bread wheat accessions, created in the past 150 years, with 45 related species. We show that many bread wheat accessions share near-identical haplotype blocks with close relatives of wheat's diploid and tetraploid progenitors, while some show evidence of introgressions from more distant species and structural variation between accessions. Hence, introgressions and chromosomal rearrangements appear to have made a major contribution to genetic diversity in cultivar collections. As gene flow from relatives to bread wheat is an ongoing process, we assess the impact that introgressions might have on future breeding strategies.


Stunting Mediates the Association between Small-for-Gestational-Age and Postneonatal Mortality.
In sub-Saharan Africa, one-third of all births are small for gestational age (SGA), and 4.4 million children are stunted; both conditions increase the risk of child mortality. SGA has also been shown to increase the risk of stunting. We tested whether the association between SGA and postneonatal mortality is mediated by stunting. We used longitudinal data from children aged 6 wk to 24 mo (n = 12,155) enrolled in the ZVITAMBO (Zimbabwe Vitamin A for Mothers and Babies) trial. HIV exposure was defined based on maternal HIV status at baseline. SGA was defined as birthweight <10th percentile of the INTERGROWTH-21st (International Fetal and Newborn Growth Consortium for the 21st Century) standards. We used a standard mediation approach by comparing the attenuation of the risk when the mediator was added to the model. We used Cox proportional hazards models first to regress SGA on postneonatal mortality, controlling for age. Stunting (length-for-age z score <-2) was then included in the model to test mediation. Approximately 20% of children were term SGA, and 23% were stunted before their last follow-up visit. In this cohort, 31% of children were exposed to HIV; the HIV-exposed group represented a pooled group of HIV-infected and HIV-exposed but uninfected children. Postneonatal mortality was significantly higher among children born SGA (HR: 1.5; 95% CI: 1.3, 1.7). This association was attenuated and not statistically significant when stunting was included in the model, suggesting a mediation effect (HR: 1.1; 95% CI: 0.91, 1.3). When stratified by HIV exposure status, we observed a significant attenuation of the risk, suggesting mediation, only among HIV-exposed children (model 1, HR: 1.3; 95% CI: 1.1, 1.6; model 2, HR: 1.1; 95% CI: 0.88, 1.3). This analysis aids in investigating pathways that underlie an observed SGA-mortality relation and may inform survival interventions in undernourished settings.